Clinical Studies Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
vaccine cannot be directly compared with rates in the clinical trials of
another vaccine, and may not reflect the rates observed in practice. There is
the possibility that broad use of CERVARIX could reveal adverse reactions not
observed in clinical trials.

Studies in Females 9 Through 25 Years of Age

The safety of CERVARIX was evaluated by pooling data from
controlled and uncontrolled clinical trials involving 23,952 females 9 through
25 years of age in the pre-licensure clinical development program. In these studies,
13,024 females (9 through 25 years of age) received at least one dose of
CERVARIX and 10,928 females received at least one dose of a control [Hepatitis
A Vaccine containing 360 EL.U. (10 through 14 years of age), Hepatitis A Vaccine
containing 720 EL.U. (15 through 25 years of age), or Al(OH)3 (500 mcg, 15
through 25 years of age)].

Data on solicited local and general adverse events were
collected by subjects or parents using standardized diary cards for 7
consecutive days following each vaccine dose (i.e., day of vaccination and the
next 6 days). Unsolicited adverse events were recorded with diary cards for 30
days following each vaccination (day of vaccination and 29 subsequent days).
Parents and/or subjects were also asked at each study visit about the
occurrence of any adverse events and instructed to immediately report serious
adverse events throughout the study period. These studies were conducted in
North America, Latin America, Europe, Asia, and Australia. Overall, the majority
of subjects were white (59.5%), followed by Asian (25.9%), Hispanic (8.5%),
black (3.4%), and other racial/ethnic groups (2.7%).

Solicited Adverse Events

The reported frequencies of solicited local injection
site reactions (pain, redness, and swelling) and general adverse events
(fatigue, fever, gastrointestinal symptoms, headache, arthralgia, myalgia, and
urticaria) within 7 days after vaccination in females 9 through 25 years of age
are presented in Table 1. An analysis of solicited local injection site
reactions by dose is presented in Table 2. Local reactions were reported more frequently
with CERVARIX when compared with the control groups; in ≥ 76% of
recipients of CERVARIX, these local reactions were mild to moderate in
intensity. Compared with dose 1, pain was reported less frequently after doses
2 and 3 of CERVARIX, in contrast to redness and swelling where there was a
small increased incidence. There was no increase in the frequency of general
adverse events with successive doses.

Table 1: Rates of Solicited Local Adverse Reactions
and General Adverse Events in Females 9 Through 25 Years of Age Within 7 Days
of Vaccination (Total Vaccinated Cohorta)

CERVARIX (9-25 years) %

HAV 720b (15-25 years) %

HAV 360c (10-14 years) %

Al (OH)3 Controld (15-25 years) %

Local Adverse Reaction

N = 6,669

N = 3,079

N = 1,027

N = 549

Pain

91.9

78.0

64.2

87.2

Redness

48.4

27.6

25.2

24.4

Swelling

44.3

19.8

17.3

21.3

General Adverse Event

N = 6,670

N = 3,079

N = 1,027

N = 549

Fatigue

54.6

53.7

42.3

53.6

Headache

53.4

51.3

45.2

61.4

GIe

27.9

27.3

24.6

32.8

Fever ( ≥ 99.5°F)

12.9

10.9

16.0

13.5

Rash

9.5

8.4

6.7

10.0

N = 6,119

N = 3,079

N = 1,027

-

Myalgiaf

48.8

44.9

33.1

-

Arthralgiaf

20.7

17.9

19.9

-

Urticariaf

7.2

7.9

5.4

-

a Total vaccinated cohort included subjects
with at least one documented dose (N).b HAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen
and 500 mcg Al(OH)3].c HAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen
and 250 mcg of Al(OH)3].d Al(OH)3 Control = control containing 500 mcg Al(OH)3.e GI = Gastrointestinal symptoms, including nausea, vomiting,
diarrhea, and/or abdominal pain.f Adverse events solicited in a subset of subjects.

Table 2: Rates of Solicited Local Adverse Reactions in
Females 9 Through 25 Years of Age by Dose Within 7 Days of Vaccination (Total
Vaccinated Cohorta)

CERVARIX (9-25 years) %

HAV 720b (15-25 years) %

HAV 360c (10-14 years) %

Al(OH)3 Controld (15-25 years) %

Post-Dose

Post-Dose

Post-Dose

Post-Dose

1

2

3

1

2

3

1

2

3

1

2

3

N

6,653

6,428

6,168

3,070

2,919

2,758

1,027

1,021

1,011

546

521

500

Pain

87.0

76.4

78.5

65.6

54.4

56.1

48.5

38.5

36.9

79.1

66.8

72.4

Pain, Grade 3e

7.5

5.6

7.7

2.0

1.4

2.0

0.8

0.2

1.6

9.0

6.0

8.6

Redness

28.4

30.1

35.7

16.6

15.2

16.1

15.6

13.3

12.1

11.5

11.5

15.6

Redness, > 50 mm

0.2

0.5

1.0

0.1

0.1

0.0

0.1

0.2

0.1

0.2

0.0

0.0

Swelling

22.8

25.5

32.7

10.5

9.4

10.5

9.4

8.6

7.6

10.3

10.4

12.0

Swelling, > 50 mm

1.1

1.0

1.3

0.2

0.2

0.2

0.4

0.3

0.0

0.0

0.0

0.0

a Total vaccinated cohort included subjects
with at least one documented dose (N).b HAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen
and 500 mcg Al(OH)3].c HAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen
and 250 mcg of Al(OH)3].d Al(OH)3 Control = control containing 500 mcg Al(OH)3.e Defined as spontaneously painful or pain that prevented normal
daily activities.

The pattern of solicited local adverse reactions and
general adverse events following administration of CERVARIX was similar between
the age cohorts (9 through 14 years and 15 through 25 years).

Unsolicited Adverse Events

The frequency of unsolicited adverse events that occurred
within 30 days of vaccination ( ≥ 1% for CERVARIX and greater than any of
the control groups) in females 9 through 25 years of age are presented in Table
3.

Table 3: Rates of Unsolicited Adverse Events in
Females 9 Through 25 Years of Age Within 30 Days of Vaccination ( ≥ 1% For
CERVARIX and Greater Than HAV 720, HAV 360, or Al(OH)3 Control) (Total
Vaccinated Cohorta)

N

CERVARIX %
N = 6,893

HAV 720b %
N = 3,186

HAV 360c %
N = 1,032

Al(OH)3 Controld %
N = 581

Headache

5.2

7.6

3.3

9.3

Nasopharyngitis

3.7

3.4

5.9

3.3

Influenza

3.1

5.6

1.3

1.9

Pharyngolaryngeal pain

2.9

2.7

2.2

2.2

Dizziness

2.2

2.6

1.5

3.1

Upper respiratory infection

2.0

1.3

6.7

1.5

Chlamydia infection

1.9

4.4

0.0

0.0

Dysmenorrhea

1.9

2.3

1.9

4.0

Pharyngitis

1.4

1.8

2.2

0.5

Injection site bruising

1.4

1.8

0.7

1.5

Vaginal infection

1.3

2.2

0.1

0.9

Injection site pruritus

1.3

0.5

0.6

0.2

Back pain

1.1

1.3

0.7

3.1

Urinary tract infection

1.0

1.4

0.3

1.2

a Total vaccinated cohort included subjects
with at least one dose administered (N).b HAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen
and 500 mcg Al(OH)3].c HAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen
and 250 mcg of Al(OH)3].d Al(OH)3 Control = control containing 500 mcg Al(OH)3.

New Onset Autoimmune Diseases (NOADs)

The pooled safety database, which included controlled and
uncontrolled trials which enrolled females 9 through 25 years of age, was
searched for new medical conditions indicative of potential new onset
autoimmune diseases. Overall, the incidence of potential NOADs, as well as
NOADs, in the group receiving CERVARIX was 0.8% (96/12,772) and comparable to
the pooled control group (0.8%, 87/10,730) during the 4.3 years of follow-up
(Table 4).

In the largest randomized, controlled trial (Study 2)
which enrolled females 15 through 25 years of age and which included active
surveillance for potential NOADs, the incidence of potential NOADs and NOADs
was 0.8% among subjects who received CERVARIX (78/9,319) and 0.8% among
subjects who received Hepatitis A Vaccine [720 EL.U. of antigen and 500 mcg Al(OH)3]
control (77/9,325).

Table 4: Incidence of New Medical Conditions
Indicative of Potential New Onset Autoimmune Disease and New Onset Autoimmune
Disease Throughout the Follow-up Period Regardless of Causality in Females 9
Through 25 Years of Age (Total Vaccinated Cohorta)

CERVARIX
N = 12,772

Pooled Control Groupb
N = 10,730

n (%)c

n (%)c

Total Number of Subjects With at Least One Medical Condition

96 (0.8)

87 (0.8)

Arthritisd

9 (0.1)

4 (0.0)

Celiac disease

2 (0.0)

5 (0.0)

Dermatomyositis

0 (0.0)

1 (0.0)

Diabetes mellitus insulin-dependent (Type 1 or unspecified)

5 (0.0)

5 (0.0)

Erythema nodosum

3 (0.0)

0 (0.0)

Hyperthyroidisme

15 (0.1)

15 (0.1)

Hypothyroidismf

30 (0.2)

28 (0.3)

Inflammatory bowel diseaseg

8 (0.1)

4 (0.0)

Multiple sclerosis

4 (0.0)

1 (0.0)

Myelitis transverse

1 (0.0)

0 (0.0)

Optic neuritis/Optic neuritis retrobulbar

3 (0.0)

1 (0.0)

Psoriasish

8 (0.1)

11 (0.1)

Raynaud’s phenomenon

0 (0.0)

1 (0.0)

Rheumatoid arthritis

4 (0.0)

3 (0.0)

Systemic lupus erythematosusi

2 (0.0)

3 (0.0)

Thrombocytopeniaj

1 (0.0)

1 (0.0)

Vasculitisk

1 (0.0)

3 (0.0)

Vitiligo

2 (0.0)

2 (0.0)

a Total vaccinated cohort included subjects
with at least one documented dose (N).b Pooled Control Group = Hepatitis A Vaccine control group [720
EL.U. of antigen and 500 mcg Al(OH)3], Hepatitis A Vaccine control
group [360 EL.U. of antigen and 250 mcg of Al(OH)3], and a control
containing 500 mcg Al(OH)3.c n (%): number and percentage of subjects with medical condition.dTerm includes reactive arthritis and
arthritis.e Term includes Basedow's disease, goiter, and hyperthyroidism.fTerm includes thyroiditis, autoimmune thyroiditis, and
hypothyroidism.g Term includes colitis ulcerative, Crohn's disease, proctitis
ulcerative, and inflammatory bowel disease.h Term includes psoriatic arthropathy, nail psoriasis, guttate
psoriasis, and psoriasis.i Term includes systemic lupus erythematosus and cutaneous lupus
erythematosus.j Term includes idiopathic thrombocytopenic purpura and
thrombocytopenia.k Term includes leukocytoclastic vasculitis and vasculitis.

Serious Adverse Events

In the pooled safety database, inclusive of controlled
and uncontrolled studies, which enrolled females 9 through 72 years of age,
5.3% (864/16,381) of subjects who received CERVARIX and 5.9% (814/13,811) of
subjects who received control reported at least one serious adverse event, without
regard to causality, during the entire followup period (up to 7.4 years).

Among females 9 through 25 years of age enrolled in these
clinical studies, 6.3% of subjects who received CERVARIX and 7.2% of subjects
who received the control reported at least one serious adverse event during the
entire follow-up period (up to 7.4 years).

Deaths

In completed and ongoing studies which enrolled 57,323
females 9 through 72 years of age, 37 deaths were reported during the 7.4 years
of follow-up: 20 in subjects who received CERVARIX (0.06%, 20/33,623) and 17 in
subjects who received control (0.07%, 17/23,700). Causes of death among
subjects were consistent with those reported in adolescent and adult female
populations. The most common causes of death were motor vehicle accident (5 subjects
who received CERVARIX; 5 subjects who received control) and suicide (2 subjects
who received CERVARIX; 5 subjects who received control), followed by neoplasm
(3 subjects who received CERVARIX; 2 subjects who received control), autoimmune
disease (3 subjects who received CERVARIX; 1 subject who received control),
infectious disease (3 subjects who received CERVARIX; 1 subject who received
control), homicide (2 subjects who received CERVARIX; 1 subject who received
control), cardiovascular disorders (2 subjects who received CERVARIX), and
death of unknown cause (2 subjects who received control). Among females 10
through 25 years of age, 31 deaths were reported (0.05%, 16/29,467 of subjects
who received CERVARIX and 0.07%, 15/20,192 of subjects who received control).

Postmarketing Experience

In addition to reports in clinical trials, worldwide
voluntary reports of adverse events received for CERVARIX since market
introduction (2007) are listed below. This list includes serious events or events
which have suspected causal association to CERVARIX. Because these events are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to vaccination.

DRUG INTERACTIONS

Concomitant Vaccine Administration

There are no data to assess the concomitant use of
CERVARIX with other vaccines.

Do not mix CERVARIX with any other vaccine in the same
syringe or vial.

Hormonal Contraceptives

Among 7,693 subjects 15 through 25 years of age in Study
2 (CERVARIX, N = 3,821 or Hepatitis A Vaccine 720 EL.U., N = 3,872) who used
hormonal contraceptives for a mean of 2.8 years, the observed efficacy of
CERVARIX was similar to that observed among subjects who did not report use of
hormonal contraceptives.